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Rachmat Gunadi WachjudiDept. Ilmu Penyakit Dalam
Fakultas Kedokteran Universitas Padjadjaran RSUP dr. Hasan Sadikin Bandung
Adverse effects Allergic & Reactions to Drugs
Adverse Drug Reactions
• Commonly found in clinical routine• Should be considered in all patients undergoing
treatment• Non-immune mediated far more common– Due to pharmacological properties– Individual predisposition:
• True allergies – T Cell mediated– IgE mediated
Classification of ADR
• Type A (pharmacological 85-90%)– Side effects– Drug interactions– others
• Type B (Hypersensitivity)– Nonspecific : defective or absent enzymes, cytokine
dysabalance, dysbalance of inflammatory mediators, non specific mast cell degranulation
– Specific immune reactions (true allergies) : Type I, Type II, Type III, Type IV
Low Birth Weight Infant• Infant less than 2500g• Glucocorticoids causes growth restriction• Prenatal excess of glucocorticoids modifies the
development of several organs, including the lung, heart, gut, and kidney
Type I IgE mediated
anaphylactic hypersensitivity,occurs within about 30 min Type II
IgG Mediated antibody- dependent cytotoxic
hypersensitivity
Type IV (Delayed type) TCell mediated
generally occur 48–72 h after antigen : monocytic,
eosinophilic, cytotoxic T cells, neutrophilic
Type III Immune complex deposition
mediated by solubleimmune complexes mostly
involving IgG antibodies
Hypersensitivities
Grading system for hypersensitivity reactions including anaphylaxis
Grade Broad clinical features Defining symptoms and signs
1 Mild
Cutaneous and subcutaneous only
Generalized erythema, periorbital edema, urticaria, or angioedema
2Moderate
Cardiovascular, respiratory, or gastrointestinal involvement
Dyspnea, stridor, wheeze, nausea, vomiting, dizziness, diaphoresis, chest or throat tightness, or abdominal pain
3Severe
Hypoxia, hypotension, orneurologic compromise
= 92 % at any stage, hypotension (systolic BP < 90 mmHg in adults), confusion, collapse, loss of consciousness, or incontinence Cyanosis or SpO2
Adapted from Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:317with kind permission from Elsevier Limited
Type I• immediate, or sometimes anaphylactic,
hypersensitivity.• Responses usually occur within 30–60 min but
can be extremely quick (within minutes) and dramatic as in anaphylaxis
Type II
• known as cytotoxic hypersensitivity and antibody-dependent cytotoxicity,
• causes reactions that are serious and potentially life-threatening.
• A number of different organs and tissues may be affected with the involvement of multiple underlying mechanisms
Type III
• Immune complex hypersensitivity• mediated by soluble immune complexes of antigen with
antibodies ( mostly of the IgG class but sometimes IgM )• Deposition of immune complexes in tissues results in a
tissue reaction initiated by complement activation that may lead to mast cell degranulation, Leukocyte chemotaxis, and inflammation induced by the cell influx.
• After exposure, reactions may develop over a period of about 3–10 h
Type IV (Delayed-Type)
• not represented by a single reaction. • Rather, it is a number of related responses
seen in a variety of reactions that may have beneficial or undesirable consequences for the host and which, at first sight, do not seem to have a lot in common except for their cellular immune base
Type IV reactions are subdivided into three categories
Type Tuberculin Contact GranulomatousTime onset 48–72 h 48–72 h 21–28 days
cells involved lymphocytes,monocytes, and macrophages
lymphocytes, macrophages
macrophages, epitheloid,and giant cells
clinical manifestations
local induration Seen as eczema as in leprosy
Urticaria and Angioedema
• 2nd most common cutaneous reaction induced by drugs (after exanthematous reactions)
• usually appearing within 36 h of drug• Exposure and resolving without sequelae
within 24 h. • occurs often in association with angioedema,
in cases of anaphylaxis and in serum sickness.• Virtually any drug can cause urticaria.
• Hives are generally raised, circumscribed, erythematous papules and plaques with a central area of pallor, often round in shape and of variable size.
• Erythematous areas may be smooth surfaced, patchy, or confluent and generalized outbreaks that may occur anywhere on the skin are extremely pruritic and transient,
• On rechallenge with drug, lesions may appear within minutes.
• Lesions that persist longer than 24 h and which are painful, burning, or leave bruising and/or pigmentation changes may indicate urticarial vasculitis
Generalized urticaria (hives)
A case of severe generalized chronic urticaria and nonlife-threatening angioedema unresponsive to anti-histamines
Angioedema
•Angioedema of the face showing non-pruritic swelling of the cutaneous tissues with some erythema.
•Angioedema persists longer than urticaria due to the accumulated fluid in the tissues.
Atlas of allergic diseases;2002;IS:08. With kind permission from SpringerScience+Business Media B.V
Contact Dermatitis
Allergic nickel contact dermatitis caused by( a) reading glasses and( b ) a multifunction key on a cellphone.
From Veien NK, in: Johansen JD, Frosch PJ,Lepoittevin J-P, editors. Contact Dermatitis. 5th ed.Berlin: Springer-Verlag; 2011. With kind permission fromSpringer Science+Business Media
Acute allergic contact dermatitis to the topical antiviral tromantadine hydrochloride showing blistering
Psoriatic Eruptions
• occur in 3.4–45 % of patients treated with lithium.
• The mechanism is currently believed to be by inhibition of the intracellular release of calcium as a result of lithium-induced depletion of inositol monophosphatase.
Generalized maculopapular exanthema
following the introduction of amoxicillin therapy showing lesions on the trunk (a) and targeted lesions on the hands and forearms ( b).
The patient had :positive (+) patch tests to
amoxicillin and ampicillin and negative (-) tests to
benzylpenicillin, dicloxacillin, and a number of cephalosporins.
AGEP • Acute Generalized Erythematous Pustulosis
• to hydroxychloroquine sulfate
Maculopapular Exanthema
Generalized maculopapular exanthema followingthe introduction of amoxicillin therapy showinglesions on the trunk( a ) and targeted lesions on the handsand forearms ( b ). The patient had positive patch tests toamoxicillin and ampicillin and negative tests to benzylpenicillin,dicloxacillin, and a number of cephalosporins.
DRESSA patient with drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS), also referred to as hypersensitivity syndrome or drug-induced hypersensitivity syndrome. The patient experienced systemic symptoms, skin reactions with nonspecific maculopapular rash, and exfoliative dermatitis with facial edema
(photograph courtesy of Dr. Adrian Mar)
Fixed Drug Eruption
• Due to drug hypersensitivity in more than 95 % of cases.
• Patients may complain of burning in the affected area before the appearance of lesions but systemic symptoms are usually absent.
• The period required for sensitization ranges from weeks to years and
• the time between drug administration and eruption can be anything from a day or two to a few weeks
Fixed Drug Eruption
• In a few cases, lesions can be so widespread that it is difficult to distinguish FDE from TEN.
• FDE is so named because the site of the eruption is FIXED
• it occurs in exactly the same place when the same drug is again encountered
Fixed Drug EruptionA fixed drug eruption showing the characteristic, often-seen circular shape. Lesions often resolve with postinflammatory pigmentation
(photograph courtesy ofDr. Adrian Mar)
A well-circumscribed bullous fixed drug eruption
The reaction was induced by carbamazepine,
a drug implicated in some severe drug-induced delayed hypersensitivity responses
Erythema Multiforme
• A self-limiting cutaneous hypersensitivity reaction to infection (mostly) or drugs
• Occurring mainly in adults 20–40 years of age ( although it can occur in patients at any age )
• Prodromal symptoms are either lacking or mild (itch, burning)
• usually resolves spontaneously in 3–5 weeks without sequelae
Erythema Multiforme
Potentially fatal, severe, rare,adverse cutaneous drug reactions
Lesions develop a central bulla and coalesce into large sheets ofnecrotic tissue covering at least 30 % of the body in the case of
Toxic Epidermal Necrolysis
Lips and facial involvement in a child with developing drug-induced Stevens–Johnson syndrome
Summary
• In the Gell and Coombs classification of allergic reactions, four types of hypersensitivities designated types I, II, III, and IV are distinguished.
• Type I, also called immediate or anaphylactic hypersensitivity, occurs within about 30 min but reactions can be dramatic and appear within seconds or minutes as in anaphylaxis.
• Type I reactions are IgE antibody-mediated. Receptor-bound drug-reactive IgE on the surface of mast cells is cross-linked by complementary drug determinants causing cell degranulation and the release of inflammatory mediators.
• Drugs well known to cause type I reactions include penicillins, cephalosporins, neuromuscular blocking drugs, some NSAIDs, monoclonal antibodies, quinolones, and proton pump inhibitors.
Urticaria
• is the second most common cutaneous reaction induced by drugs, often in association with angioedema and anaphylaxis.
• Many drugs are implicated including β-lactams, NSAIDs, sulfonamides, vancomycin, and contrast media. ACE inhibitors are responsible for approximately one in six patients admitted to hospital with angioedema.
Type II hypersensitivity
• is also known as antibody- dependent cytotoxic hypersensitivity. Drugs can attach to cell membranes producing drug-induced hemolytic anemia, thrombocytopenia, and granulocytopenia.
• Drugs implicated: – hemolytic anemia—penicillins, quinidine, methyldopa; – thrombocytopenia—quinine, quinidine, propyl
thiouracil, vancomycin, sulfonamides; – granulocytopenia—pyrazolones, thiouracil,
anticonvulsants, and sulfonamides.
Type III hypersensitivity
• is mediated by soluble immune complexes mostly involving IgG antibodies.
• Drug-induced serum sickness-like reaction is the prototype example of type III drug hypersensitivity.
• Hypersensitivity vasculitis is another example of a type III hypersensitivity response induced by drugs.
Type IV hypersensitivity reactions • are mediated by antigen-specific effector T cells. Reactions
generally occur 48–72 h after antigen exposure and are therefore referred to as delayed reactions.
• Important delayed cutaneous reactions include – maculopapular exanthema; – allergic contact dermatitis; – psoriasis; – acute generalized exanthematous pustulosis; – drug reaction with eosinophilia and systemic symptoms; – fixed drug eruption – erythema multiforme; – Stevens–Johnson syndrome; – toxic epidermal necrolysis.
Summary Type I Type II Type III Type IV
Other designations
Immediate; anaphylactic
Cytotoxic Immune complex
Delayed; cell- mediated; T cell mediated
Time for reaction
Seconds to 30 min
Hours (~1 day) 3–10 h 24–72 h
Examplesof disease states
Erythema; urticaria;angioedema;respiratory symptoms;GI symptoms;anaphylaxis
Drug-inducedhemolytic anemia,thrombocytopenia, agranulocytosis(immune form)
Serum sickness;Drug-inducedvasculitis
Allergic contactdermatitis; Psoriasis;Maculopapularexanthema; AGEP;FDE; SJS; DRESS; TEN; EM
Type Drugs ImplicatedI ß-Lactams; some NSAIDs; quinolones; mAbs; PPI
II ß-Lactams; quinine; quinidine; sulfonamides; NSAIDs; procainamide; gold; carbamazepine; PTU;
III ß-Lactams; ciprofloxacin; sulfonamides; lincomycin; tetracycline; NSAIDs; carbamazepine; allopurinol; gold; methyldopa; mAbs
IV NSAIDs; ß-lactams; other antibiotics; anticonvulsants; antimalarials; local anesthetics; barbiturates; quinolones; dapsone
Summary
Type Drugs ImplicatedI ß-Lactams; some NSAIDs; quinolones; mAbs; PPI
II ß-Lactams; quinine; quinidine; sulfonamides; NSAIDs; procainamide; gold; carbamazepine; PTU;
III ß-Lactams; ciprofloxacin; sulfonamides; lincomycin; tetracycline; NSAIDs; carbamazepine; allopurinol; gold; methyldopa; mAbs
IV NSAIDs; ß-lactams; other antibiotics; anticonvulsants; antimalarials; local anesthetics; barbiturates; quinolones; dapsone
Reference
• B.A. Baldo and N.H. Pham, Drug Allergy: Clinical Aspects, Diagnosis, Mechanisms, Structure-Activity Relationships, DOI 10.1007/978-1-4614-7261-2_2, © Springer Science+Business Media, LLC 2013
• O Hausmann, B Schnyder, WJ Pichler : Etiology and pathogenesis of adverse drug reactions. Chem Immunol Allergy. Basel. Karger. 2012.vol 97, pp 32-46